tbuckley/cabot-search huggingface dataset:
P033: Clinical significance of the severity of THRLBCL-like areas in nodular lymphocyte predominant Hodgkin lymphoma
Authors: Irirna Shupletsova, Alla Kovrigina, Elena Dorokhina, Tatyana Moiseeva
Journal: HemaSphere (2022)

Table 1: Comparison of clinical parameters in 3 subgroups of patients with non-classical subvariants (non-A/B) depending on the value of THRLBCL areas (0%, 0>%<50%, ≥ 50%) Introduction: According to the WHO 2017 the presence of sites resembling T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) does not refer to transformation into THRLBCL. Objective: To compare the severity of THRLBCL-like areas in NLPHL with the clinical course of the disease. Materials and Methods: The study group included 59 patients with verified diagnosis (morphology, IHC) of NLPHL (2010–2017, NRCH for hematology): m/f ratio 3.4: 1, median age - 35 (range 17–68), with biopsy material of lymph node/other localization of the primary biopsy in the debut of the disease. The severity of THRLBCL-like areas was analyzed using IHC with CD20 antibodies and empirically selected cut off of these sites in 50%, compared with clinical and instrumental data. Results: Patients with non-classical subvariants (non-A/B, n=42) were divided into 3 subgroups: 1 subgroup 0% (17/42), 2 subgroup - 0>%<50% (11/42), 3 subgroup ≥50% (14/42) THRLBCL-like areas of the area of the lymph node section. In the three analyzed subgroups, there were a significant difference in the frequency of diagnosis of stage IV of the disease (p=0.0507), bone marrow damage (p=0.0005) and spleen (p=0.0101), response to first-line therapy (p=0.0126). Table 1. In the subgroup with the presence of THRLBCL-like areas ≥50%, up to 6 affected extranodal localizations were observed: bone marrow trephine biopsies, spleen, liver, paravertebral soft tissues, bones, thyroid gland. Conclusions: A subgroup of patients with the presence of THRLBCL-like areas ≥50% of the area of the lymph node section is characterized by the most unfavorable clinical course of the disease.
P077: Predicting radiotherapy dose to the heart and the risk of radiation-related cardiac toxicity for Hodgkin lymphoma patients, using pre-chemotherapy PET-CT scans
Authors: Rebecca Shakir, Victoria Butterworth, Georgios Ntentas, Johanna Ramroth, David Cutter
Journal: HemaSphere (2022)

Figure 1: Scatter plot of the 30-year cumulative absolute excess risk of ischaemic heart disease calculated using the mean heart dose predicted by the model and that calculated using the mean heart dose measured on the radiotherapy treatment plan Background: Consolidative radiotherapy (RT) used to treat early-stage Hodgkin lymphoma (HL) reduces the chance of recurrence [1], but may cause late toxicity including cardiovascular disease (CVD) [2]. The risk of CVD can be estimated from the radiation dose received by the heart from RT, but currently this is only known once a RT plan has been produced. The aim of this study was to develop a model to predict the dose the heart would receive, and thereby the risk of CVD, from RT using information available at the time of HL diagnosis. Methods: The cohort was 169 patients treated with RT who had pre-chemotherapy PET-CT scans (pcPET-CT); 83% had stage 2 disease, and 91% had primary rather than relapsed HL. For each patient, the distribution of HL on the pcPET-CT was documented, and the mean heart dose (MHD) extracted from the RT plan. A multivariable linear regression model was built to predict MHD. Predicted MHDs were used in combination with a dose-response relationship for the risk of ischaemic heart disease (IHD) [3], and background IHD rates, to estimate absolute excess risk (AER) of IHD from RT. Results: The model that best predicted MHD included the extent to which HL overlapped the heart, presence of hilar disease, width of mediastinal disease, RT delivery technique and breathing mode. The mean prediction error was 2.9 Gray (Gy) (range 0.2 to 12.1). Individual patient AER of IHD calculated using the predicted MHD were closely correlated with the AER calculated using the RT plan MHD (Figure 1). AERs calculated using the MHD from each method were not statistically significantly different (paired t-test p=0.88; mean within-patient difference 0.9%). Conclusion: Patient-specific risks from consolidative RT can be estimated using pcPET-CT. Work is ongoing to refine this model using a larger dataset, and develop models to predict other organ doses and associated risks. If validated, such estimates could inform shared decision-making about the use of RT to treat an individual with HL. References 1. Shaikh MP et al. Consolidation radiotherapy following positron emission tomography complete response in early-stage Hodgkin lymphoma: a meta-analysis. Leuk Lymphoma 2020;0:1 2. Gustavsson A et al. A systematic overview of radiation therapy effects in Hodgkin’s lymphoma. Acta Oncol (Madr) 2003;42:589 3. van Nimwegen FA et al. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol 2016;34:235
P016: Reduced steroid exposure is safe and does not reduce disease control among Hodgkin Lymphoma patients treated with escalated BEACOPP (eBEACOPP)
Authors: Ida Hude Dragičević, Sandra Bašić-Kinda, Dino Dujmović, Ivo Radman, Barbara Dreta, Sandra Dotlić, Lea Galunić-Bilić, Margareta Dobrenić, Marko Kralik, Pavle Rončević, Igor Aurer
Journal: HemaSphere (2022)

Figure 1: PFS (Kaplan-Meier curves): The outcome of EU and AS patients - 5-y PFS 95% vs. 98%, respectively. Full-length vs. shorter steroid courses - 5 y PFS 98% vs. 95%, respectively. Background: eBEACOPP is the most effective chemotherapy regimen for younger patients with early unfavourable (EU) and advanced stage (AS) Hodgkin lymphoma (HL), but is burdened with early and late toxicities. The original 14 days of steroids contributes to side effects, including severe osteoarticular events, like avascular bone necrosis (AVN). We have been using eBEACOPP since 2009 for AS and since 2014 also for EU patients. We started reducing the length of steroid treatment to 8–10 days in 2016, primarily to reduce the risk of AVN. Methods: We analysed outcomes of our patients, focusing on the comparison of EU and AS patients and those receiving full length and shorter steroid courses. Data was obtained retrospectively, from the hospital database. Results: 162 patients received eBEACOPP as front-line treatment, 130 with AS and 32 with EU HL. Median age was 31 y, range 19–59; 88 (54%) were male. After a median follow-up of 58 mo, 5-y PFS of the whole cohort was 97% and OS 98%. The outcome of EU and AS patients was indistinguishable with a 5-y PFS of 95% vs. 98%, respectively (Fig). Outcome of patients receiving full-length or shorter steroid courses was also indistinguishable, with a 5 y PFS of 98% vs. 95% respectively (Fig). The incidence of AVN was numerically, but statistically insignificantly lower in patients receiving 6 cycles of eBEACOPP with a shorter steroid course (1/42 vs. 4/72, p=0.65). There were no differences in emergency hospital admissions and episodes of febrile neutropenia between the two cohorts. Conclusion: eBEACOPP provides excellent and durable first line disease control. Our data confirms the findings of GHSG of lack of outcome differences between different prognostic groups if eBEACOPP is used as primary treatment. Reducing the duration of steroid treatment to 8 days per cycle is safe, but longer follow-up and more patients are needed to confirm that it reduces serious acute and chronic toxicities.
P070: Design of the INSIGHT study, evaluation of long-term follow-up care for lymphoma survivors in the Netherlands: does survivorship care at the BETER clinics reduce morbidity and mortality from late effects of lymphoma treatment and associated costs?
Authors: Annelies Nijdam, Eline M.J. Lammers, Berthe M. P. Aleman, Josée. M. Zijlstra, Flora E. Van Leeuwen
Journal: HemaSphere (2022)

Background: Hodgkin lymphoma (HL) survivors are at substantial risks of serious late adverse treatment effects. The BETER consortium developed a nationwide infrastructure of outpatient clinics where 5-year HL survivors are screened and treated for adverse effects of lymphoma treatment according to nationally approved screening guidelines. BETER survivorship care includes risk-based screening for and treatment of (risk factors for) cardiovascular disease (CVD), breast cancer, hypothyroidism and (functional) asplenia. So far, evidence for the actual cost-effectiveness of structured cancer survivorship care in clinical practice is lacking. Current knowledge is based on simulation and modelling approaches and evidence from other populations (e.g. BRCA mutation carriers). In the INSIGHT study we will assess the (cost-)effectiveness of BETER survivorship care using data from clinical practice. Methods: The first BETER clinics started in 2013–2016 and the number of centres participating in BETER is quickly expanding: several centres started/will start a BETER clinic in 2021–2024. This allows for a retrospective cohort study with a quasi-experimental design to evaluate the effectiveness of BETER survivorship care by comparing survivors who did and did not receive BETER survivorship care. Once full nationwide implementation is in place, this comparison is no longer possible. In the INSIGHT study we will compare 450 HL survivors invited for BETER survivorship care in 2013–2016 with 450 matched survivors invited by a BETER clinic starting in 2021–2024, allowing for a median follow-up of ~8 years. The primary outcomes are burden of disease (in disability-adjusted life-years, DALYs) from CVD, breast cancer, hypothyroidism and (functional) asplenia, associated health care costs, quality of life and health-related productivity losses. Secondary outcomes are BETER clinic attendance, guideline adherence and knowledge and risk perception of late effects. In a cost-effectiveness analysis we will calculate costs/DALY and costs/QALY of BETER survivorship care. Conclusion: BETER is an internationally unique initiative of an elaborate infrastructure for adult oncology survivorship care. To our knowledge, INSIGHT is the first evaluation of (cost-)effectiveness of cancer survivorship care in clinical practice. The results will contribute to more effective, evidence-based long-term cancer survivorship care. At ISHL12 we will present design details as well as participation rates.
T100: Long term Follow-up of a Phase I Study Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A trial of the ECOG-ACRIN Research Group (E4412: Arms A-I)
Authors: Catherine Diefenbach, Opeyemi Jegede, Richard Ambinder, Jonathon Cohen, Michael Robertson, Kevin David, Ranjana Advani, Timothy Fenske, Stefan Barta, Neil Palmisiano, Jakub Svoboda, David Morgan, Reem Karmali, Brad Kahl, Stephen M. Ansell
Journal: HemaSphere (2022)

Figure 1: E4412 Response: DOR (A), PFS (B), OS (C) Background: E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of brentuximab (BV), nivolumab (N), and ipilimumab (I) in patients with R/R HL. Here we present the long-term safety and response data on the full cohort of patients treated in Phase 1 (Arms A-I). Methods: Patients with confirmed R/R HL were treated in sequential dose escalation cohorts using 3 + 3 design. Additional patients were enrolled in expansion cohorts. Dose limiting toxicity (DLT) was evaluated within the first cycle of therapy. Results: Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; 3 patients were excluded due to ineligibility after enrolment. Thirty-five patients (57%) were refractory to their prior therapy; twenty-one (34%) had autologous stem cell transplant (SCT), 4 (6%) had prior alloSCT. Eight patients (13%) had prior BV. Safety: All 64 enrolled patients are included in the safety analysis. The most common (>30%) treatment-related grade 1–2 AEs were: nausea, peripheral sensory neuropathy, diarrhea, fatigue, elevated liver transaminases, anemia, and rash. Grade 3+ rash was more common in BV-I, in 22% of 23 patients compared with 7% of 41 patients in the other groups. Grade 3–4 events occurred in ten (43%) patients on BV-I, three (16%) patients on BV-N, and 12 (55%) patients in the triplet group. Two (3%) patients had treatment related death, one on BV-N (pneumonitis) and one in the BV-N-I group (dyspnea). Response: The overall response rate (ORR) was 76% for BV-I, with a complete remission (CR) rate of 57%, for BV-N the ORR was 89% with a CR rate of 61% and for BV-N-I the ORR was 82% with a CR rate of 73%. The median follow-up (Q1, Q3) for PFS and OS is 2.24 (1.67, 2.72) years and 2.98 (2.83, 3.04) years. Duration of response (DOR) is 1.32 years for BV-I responders, not reached for BV-N and BV-N-I responders (Figure 1A). The median PFS is 1.1 years, NR, and 2.49 years for BV-I, BV-N and BV-N-I respectively (Figure 1B). The median OS has not been reached for any of the arms (Figure 1C). Conclusion: Long term data from the Phase 1 component of E4412 shows no late safety concerns, and significant durability of response in both N containing arms with median follow-up of nearly 3 years. Analysis of the impact of transplant and depth of response will be updated by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-N to the triplet of BV-N-I.
P106: Dose intensive brentuximab vedotin for platinum resistant recurrent Hodgkin lymphoma is a feasible treatment option - a single center experience
Authors: Axel Erenmalm, Johan Linderoth
Journal: HemaSphere (2022)

Since 2013, mainly before the introduction of PD-1 inhibitors, we treated Hodgkin lymphoma (HL) patients failing to respond with a complete metabolic remission (CR) after first salvage treatment with a dose intense regimen of 1.2 mg/kg brentuximab vedotin (BV) given days 1, 8, 15 in a 28-day cycle. Patients achieving CR after one cycle received another cycle and proceeded to high dose chemotherapy (HDCT) with autologous stem cell transplant. Patients not reaching metabolic CR received other treatments. Ten patients were treated with dose intense BV, five patients with primary refractory disesease/early relapse and five patients with later relapses. First salvage regimens were IME x 2 (1 patient), DHAP 2–4 cycles (5 patients), IME x 2 + 2–4 cycles DHAP (2 patients) and ICE x 2–4 (2 patients). Of the five patients with refractory disease/early relapse, four patients had satisfactory responses and proceeded to HDCT. One patient progressed and received radiotherapy instead. Four patients of five with later recurrent disease had satisfactory responses and proceeded to HDCT. For one patient with insufficient response, bendamustine was added to BV 1.8 mg/kg and given in further three cycles before HDCT. One patient with PET-positive disease after ICE x 2 and possibly concurrent tuberculosis was for this reason treated with a PD1-inhibitor for 9 months, progressed, received dose intense BV with good effect and proceeded to HDCT. In total 8/10 (80 %) responded satisfactorily to dose intense BV. The patient who was not treated with HDCT later succumbed to the disease, and two patients with late relapses have had new relapses. The rest of the patients are free of recurrence. Consolidative treatment after HDCT was given with radiotherapy in two cases and maintenance BV in another two cases. Median follow up is 67 months after ASCT. Side effects have been mild, mostly grade 1 neuropathy. For one patient with grade 1–2 neuropathies already on primary treatment with ABVD, dose reduction was made to 90 % in the second cycle of induction BV and to 66% for the six cycles of maintenance BV given. For another patient maintenance BV was stopped after 4 cycles due to grade 2 neuropathy. Conclusion: According to our experience dose intense BV is an effective and feasible treatment option for HL patients with platinum resistant recurrent disease. We suggest that this way of using BV should be studied in the context of insufficient response to PD-1 inhibitors pre-HDCT.
T026: Characterization of cancer-associated fibroblasts in classical Hodgkin lymphoma
Authors: Kristiina Karihtala, Suvi-Katri Leivonen, Marja-Liisa Karjalainen-Lindsberg, Arne Östman, Teijo Pellinen, Sirpa Leppä
Journal: HemaSphere (2022)

Background: Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population with diverse functions. They constitute an important stromal component of the tumor microenvironment (TME), regulate immune responses and promote tumor growth. We have earlier characterized the immunoprofile of cHL and concluded that high proportions of checkpoint protein positive immune cells associated with unfavorable overall survival (OS). Here, we have characterized distinct CAF subsets and their clinical impact in cHL. Methods: CAFs, tumor associated macrophages (TAMs), T cells and checkpoint molecules were phenotyped from the diagnostic cHL samples (n=131) using multiplex immunohistochemistry with digital image analysis. Platelet-derived growth factor receptor (PDGFR) α and β, fibroblast-activation protein (FAP) and α-smooth muscle actin (α-SMA) were utilized as CAF markers. Nanostring-based data from a 770-gene immune panel was used to correlate CAF proportions with gene expression. Results: Median age of the patients was 30 years, 78% had nodular sclerosis subtype and 56% advanced stage. Primary treatment (85%) was mostly doxorubicin, bleomycin, vinblastine, dacarbazine, and in limited stage, in combination with radiotherapy. At the median follow-up time of 55 months, 22% of the patients relapsed and 8% died. Five-year freedom from treatment failure (FFTF) was 79% and OS 91%. From all cells in the TME, 20% were PDGFRβ (range 0.2–92%), 19% FAP (range 0–88%), 16% α-SMA (range 2–56%), and 1% PDGFRα (range 0.1–58%) positive. High proportion of FAP+ cells associated with inferior FFTF (HR 1.25, 95%CI 1.0–1.5, P=0.020). In a small subgroup of patients, PDGFRα and FAP were expressed on the same cells defining an PDGFRα+FAP+ double positive cHL phenotype, which translated to better outcome (5-y FFTF 100 % vs. 76%, P=0.035; 5-y OS 100% vs. 90%, P=0.270). Clinical characteristics were equally distributed between these subgroups. PDGFRα+FAP+ phenotype associated positively with high proportion of TAMs (P=0.026), but negatively with T cells (P=0.006) and checkpoint molecule indoleamine 2,3 dioxygenase 1 (IDO-1)+ cells (P=0.002). In addition, focal adhesion and extracellular matrix pathway genes were enriched in PDGFRα+FAP+ cHLs. Conclusion: Our data identifies distinct CAF subsets in cHL and suggests that the newly characterized subset of PDGFRα+FAP+ CAFs has prognostic impact in cHL patients. Validation of the results is ongoing.
P040: LINE-1 reverse transcriptase activity in Hodgkin lymphoma cells
Authors: Annika Wadel, Leonie Jaster, Martin S. Staege
Journal: HemaSphere (2022)

Background: The human genome contains a large number of repetitive elements including endogenous retroviruses and long interspersed nuclear elements (LINE). Repetitive elements have been shown to be activated and influence gene expression in Hodgkin lymphoma (HL). Some repetitive elements contain open reading frames that encode a reverse transcriptase. We analyzed RT activity and expression of reverse transcriptase sequences in HL cells. Methods: RNA seq analysis was used for the identification of expressed putative reverse transcriptases in HL cells. Reverse transcriptase activity in HL cells was assessed using phage MS2 RNA as template for reverse transcription and amplification by quantitative polymerase chain reaction. Sensitivity of HL cells for the non-nucleoside reverse transcriptase inhibitor efavirenz was analyzed by flow cytometry. LINE-1 reverse transcriptase sequences were amplified from HL cell line L-428 by reverse transcription-polymerase chain reaction, cloned into vector pGEM-T Easy and sequenced by Sanger sequencing. Results: HL cells showed high reverse transcriptase activity in comparison to normal blood cells. In addition, efavirenz killed HL cells in a dose dependent manner. RNA seq analysis suggested that HL cells express sequences corresponding to LINE-1 reverse transcriptase. By RT-PCR using LINE-1 reverse transcriptase specific primers, several transcripts containing open reading frames with predicted coding capacity for reverse transcriptase molecules were identified. Conclusions: HL cells express LINE-1 reverse transcriptase sequences that might be responsible for the observed reverse transcriptase activity of these cells. LINE-1 reverse transcriptase might be interesting targets for future therapeutic developments. Our work is supported by Mitteldeutsche Kinderkrebsforschung.
P047: Predictive role of the Hodgkin lymphoma-associated cytokines: a prospective study of the Czech Hodgkin Study Group
Authors: Vit Prochazka, Heidi Mocikova, Alice Sykorova, Jana Markova, Marie Lukášová, Lubica Gaherova, Alexandra Kredatusova, Eva Kriegova, Maria Maco, Tomas Kozak, David Belada, Tomas Papajik
Journal: HemaSphere (2022)

Figure 1: PFS stratified by the pretreatment levels of sCD30 (left) and sIL-6 (right) Background: Prognostic stratification and thus the selection of the frontline treatment in Hodgkin lymphoma (HL) is based on historical systems which only indirectly reflect lymphoma burden or cytokine activity. Analysis of the lymphoma-related soluble biomarkers offers a non-invasive tool for more precise risk stratification. Aim: To define a prognostic significance of the pretreatment soluble cytokines levels in the newly diagnosed pts with HL treated within GHSG policy Methods: We have conducted prospective serum sampling (2017–2021) of the unselected pts treated in three university hospitals in the Czech Republic. All samples were analysed centrally using ELISA for lymphoma cells (TARC pg/ml; sCD30, ng/ml), macrophages (sCD163, ng/ml) and inflammation-related cytokines (sIL-6, pg/ml). Clinical and laboratory data were retrieved from the national Hodgkin lymphoma registry. Results: In total we have analysed 169 (100%) consecutive pts. Median age was 42 (19–83) yrs, with slight female predominance (52%). All but 7 pts (96%) have been diagnosed as classical HL (nodular sclerosis in 83, mixed cellularity in 58, lymphocyte-rich in 8 and lymphocyte depletion in 1, 12 not classified). Ann Arbor stages were as follows: (12%), II (37%), III (22%), IV (29%) with B-symptoms present in (56%) and extranodal disease in (32.5%) of the pts, leading to allocating of the pts into limited (18%), intermediate (24%) and advanced (58%) GHSG stages. Treatment was based on ABVD (48%), BEACOPPesc (42%), COPP/ABV (8%), or other (2%) regimen. Treatment response was assessed in 161 pts (95%), with CR in 90 % of the pts. After a median FU of 43 months the 5-y OS reached 90.4% (95% CI 0.83–0.98) and 5-y PFS 86.6% (95% CI 0.81–0.93). Lower mean pretreatment levels of 3 cytokines correlated with achieving of CR: sCD30 (70 vs 130; p=0.04), sCD163 (783 vs 1171; 0.007), sIL-6 (26 vs 130; p<0.001), TARC did not show any correlation with CR (mean 33764 vs 23702; p=0.67). Two cytokines were predictive for PFS: sCD30, cut-off 90 ng/ml (5-y PFS 79.1 vs 90.4%; p=0.044) and sIL-6, cut-off 9 pg/ml (5-y PFS 80.3 vs 92.5%; p=0.023). High levels of sCD30 and sIL-6 were associated with inferior 5-y OS of 79.3 vs 97.2% (sCD30, p=0.004) and 82.6% vs 97.4 % (sIL-6, p=0.025). Conclusion: Pretreatment levels of soluble CD30 and IL-6 are associated with the treatment outcome and survival in the patients treated with GHSG risk-adapted policy. Acknowledgment MZCR-RVO (FNOL, 00098892), AZV NU22-03-0018